Inflammatory and coagulation biomarkers and mortality in patients with HIV infection.
BACKGROUND
In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.


RESULTS
Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.


CONCLUSIONS
IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.
Kuller
Lewis H
LH
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Tracy
Russell
R
Belloso
Waldo
W
De Wit
Stephane
S
Drummond
Fraser
F
Lane
H Clifford
HC
Ledergerber
Bruno
B
Lundgren
Jens
J
Neuhaus
Jacqueline
J
Nixon
Daniel
D
Paton
Nicholas I
NI
Neaton
James D
JD
D019380:Anti-HIV Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood*; D001777:Blood Coagulation; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D002423:Cause of Death; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005500:Follow-Up Studies; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000401:mortality*; D006801:Humans; D007249:Inflammation / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016015:Logistic Models; D008297:Male; D015337:Multicenter Studies as Topic; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D000685:Serum Amyloid A Protein / Q000032:analysis; D000683:Serum Amyloid P-Component / Q000032:analysis; D015996:Survival Rate; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; D000685:Serum Amyloid A Protein; D000683:Serum Amyloid P-Component; C036309:fibrin fragment D; D002097:C-Reactive Protein